Serum Igd and Ige Concentrations in Immunodeficiency Diseases

Serum IgD and IgE concentrations in immunodeficiency diseases.

R H Buckley, S A Fiscus

J Clin Invest. 1975;55(1):157-165. https://doi.org/10.1172/JCI107906.

Research Article

Concentrations of IgD and IgE were measured in sera from 165 patients with well-defined immunodeficiency in an effort to find information possibly relevant to the roles of antibodies of these classes in host defense. Values for both immunoglobulins were generally quite low in patients who had marked deficiencies of all three major immunoglobulins, although occasional normal or high normal values for IgD were seen in hypogammaglobulinemic patients. Group mean IgD concentrations were also depressed in patients with Wiskott-Aldrich syndrome and in those with selective IgA deficiency; IgE concentrations were depressed in patients with X-linked immunodeficiency with hyper-IgM and in those with ataxia telangiectasia. IgD and IgE were both significantly elevated in patients with extreme hyperimmunoglobulinemia E and undue susceptibility to infection and in a patient with the Nezelof syndrome; none of these patients had histories suggestive of atopy. In addition, the mean IgE concentration was significantly elevated in patients with selective IgA deficiency, many of whom were atopic, and in those with the Wiskott-Aldrich syndrome. The highest IgD concentration (163 mg/100 ml) was found in serum from a boy with variable immunodeficiency who had a lifelong history of severe recurrent pharyngeal infections, primarily streptococcal in etiology. Recurrent staphylococcal infection was a feature common to many but not all patients with elevated serum IgE concentration. These data may prove useful in […]

Find the latest version: https://jci.me/107906/pdf Serum IgD and IgE Concentrations in Immunodeficiency Diseases

REBECCA H. BUCKLEY and SUSAN A. Fiscus From the Departments of Pediatrics and Microbiology and Immunology, Duke University School of Medicine, Durham, North Carolina 27710

A B S T R A C T Concentrations of IgD and IgE were munoglobulins, IgG, IgA, and IgM, in patients with measured in sera from 165 patients with well-defined immunodeficiency (1). Less is known, however, about immunodeficiency in an effort to find information pos- concentrations of IgE in such patients (2-10), and in- sibly relevant to the roles of antibodies of these classes formation on IgD concentrations in immunodeficiency in host defense. Values for both immunoglobulins were can be found primarily only in limited studies (2, 11, 12) generally quite low in patients who had marked defi- or case reports (13). Considerable knowledge has been ciencies of all three major immunoglobulins, although derived from the study of patients with immunodefi- occasional normal or high normal values for IgD were ciency diseases about the host defense roles played by seen in hypogammaglobulinemic patients. Group mean various components of the immune system. Since it is IgD concentrations were also depressed in patients with unknown whether antibodies of the IgD and IgE classes Wiskott-Aldrich syndrome and in those with selective function in host defense, knowledge of deficiencies or IgA deficiency; IgE concentrations were depressed in elevations of these proteins in particular groups of in- patients with X-linked immunodeficiency with hyper- fection prone immunodeficient patients may provide IgM and in those with ataxia telangiectasia. IgD and IgE some clues as to their biologic function. In the case of were both significantly elevated in patients with extreme IgD antibodies no clearly identifiable biologic activity hyperimmunoglobulinemia E and undue susceptibility to has yet been found, and indeed, there are only a few infection and in a patient with the Nezelof syndrome; reports of antibody activity in molecules having the none of these patients had histories suggestive of atopy. antigenic properties of IgD (14-17). It is known, how- In addition, the mean IgE concentration was signifi- ever, that IgD molecules do not cross the placenta, are cantly elevated in patients with selective IgA deficiency, not present in body secretions or urine (12), and do not many of whom were atopic, and in those with the Wis- fix complement or sensitize guinea pig skin for passive kott-Aldrich syndrome. The highest IgD concentration cutaneous anaphylaxis (18, 19). IgE antibodies do not (163 mg/100 ml) was found in serum from a boy with cross the placenta or fix complement but are known to be variable immunodeficiency who had a lifelong history present in external secretions and to bind to basophils of severe recurrent pharyngeal infections, primarily and mast cells (20). IgE antibodies so bound effect the streptococcal in etiology. Recurrent staphylococcal in- release of histamine and the slow reacting substance of fection was a feature common to many but not all pa- anaphylaxis upon combination with antigen, causing tients with elevated IgD and IgE. Depressed cell-medi- both anaphylactic and atopic types of immediate hyper- ated immunity was present in many patients with ele- sensitivity. vated serum IgE concentrations. These data may prove In the present study we examined serum IgD and IgE useful in the future delineation of biologic roles for concentrations in 165 patients who represent a spectrum antibodies in these two immunoglobulin classes. of well-defined immunodeficiency diseases. While these proteins were found generally to be present in low concentrations when there were marked deficiencies in the INTRODUCTION other three immunoglobulin classes, some immunodefi- Numerous reports have documented a wide variety of cient patients were found to have elevated concentrations abnormalities in concentrations of the three major im- of IgD, IgE, or both. Knowledge of clinical features of several of the latter patients may prove useful in the Received for publication 4 June 1974 and in revised future delineation of biologic roles for antibodies in these form 3 September 1974. two immunoglobulin classes. The Journal of Clinical Investigation Volume 55 January 1975-157-165 157 METHODS rose to detect antiruminant antibodies which would give false positive rings of precipitate (22) ; all sera reacting Study population. Venous blood samples were obtained on these plates were absorbed with normal goat serum from 165 patients with well-defined immunodeficiency; the until they no longer gave rings of precipitate and then sera were separated by centrifugation and stored at -200C were retested. until studied. Most of the patients were seen and/or fol- IgE concentrations were measured by two methods. Sera lowed at the Duke University Medical Center from 1967 were screened initially for high IgE values with commer- to 1974, but a few were seen by physicians elsewhere who cially available goat antihuman IgE agarose plates (Meloy mailed the patients' sera to us. The deficiency group was Laboratories Inc.) which permitted measurement of con- composed of 10 cases of infantile X-linked agammaglobu- centrations as low as 697 U/ml. All sera which had no linemia (X Ag),' 15 patients with non-X-linked agamma- detectable IgE by single radial diffusion were tested by a globulinemia (Non-X Ag), 8 infants with transient hypo- modification of the double antibody method of Gleich, Aver- gammaglobulinemia (Trans Ag), 3 patients with X-linked beck, and Swedlund (23) which was capable of detecting immunodeficiency with hyper-IgM (Hyp M), 9 infants with IgE concentrations less than 1 U/ml. In the early part of severe combined immunodeficiency (SCID), 79 patients this study, the reagents employed in the assay included: with selective IgA deficiency (A Def), 7 cases of ataxia (a) sheep anti-IgE (ND) antiserum, kindly provided by telangiectasia syndrome (A-T), 3 patients with cellular Dr. David S. Rowe of the WHO International Reference immunodeficiency with normal or hyperimmunoglobulinemia Center for Immunoglobulins; (b) rabbit antigoat IgG pre- (Nezelof syndrome or Nez), 4 examples of immunode- pared by immunizing 12 rabbits with DEAE cellulose puri- ficiency with thrombocytopenia and eczema (Wiskott-Al- fied goat IgG and repeatedly absorbing the pooled antisera drich syndrome or W-A) (1), 11 patients with the syn- with normal human serum; and (c) purified IgE (PS), drome of extreme hyperimmunoglobulinemia E and undue isolated by ion exchange and gel filtration chromatography susceptibility to infection (Hyp E) (4), 6 patients with from serum obtained from Dr. 0. Ross McIntyre and other forms of variable immunodeficiency (Var ID), and labeled with 12"I by the method of Hunter and Greenwood 10 cases of chronic granulomatous disease of childhood (24). When antiruminant antibodies present in many of the (CGD). study patients' sera (especially those with either A Def Normal controls for serum IgD concentrations consisted or W-A) were found to give falsely high results in this of 23 infants, 105 children, and 57 adults; normal controls modification, the method required further revision so as to for serum IgE concentrations included 12 infants, 55 chil- eliminate ruminant antisera. Assays involving sera con- dren, and 51 adults. These subjects were selected from taining antiruminant antibodies or sera from patients en- hospital personnel and patients attending the Duke Pediatric tering the study during the latter part included the follow- Outpatient and Cardiac Clinics. Verbal informed consent ing reagents: (a) rabbit anti-Fc IgE, raised against PS was obtained for the venous blood collections. Inquiry was Fc fragment isolated by agarose block electrophoresis of made about personal histories of recurrent infection, para- papain-digested, purified PS, (b) pony antirabbit IgG, pre- sitism, atopic disorders, or autoimmune diseases, and individ- pared by immunizing a pony with DEAE cellulose purified uals with positive histories were excluded. rabbit IgG and repeatedly absorbing the antiserum with Measurement of IgD and IgE. Concentrations of IgG, normal human serum, and (c) purified Bedore IgE mye- IgA, and IgM were determined by single radial diffusion loma protein, obtained from Dr. Roy Wood of the Immuno- using antisera specific for each of these human immunoglobulin Reference Center, Springfield, Va. and radiolabeled globulins and primary reference standards prepared in this as above. Serum from one of the study patients (B. S.) laboratory (21). IgD concentrations were measured by a with extreme hyperimmunoglobulinemia E and undue sus- similar method using commercial goat anti-human IgD ceptibility to infection (4) was calibrated against a research agarose plates (Meloy Laboratories Inc., Springfield, Va.). standard (68/341) for IgE, obtained from the WHO The secondary IgD reference standard was calibrated Reference Center for Immunoglobulins, and found to have against a research IgD standard (67/37) obtained from 22,300 U/ml. B. S. serum was used as the secondary refer- the WHO Reference Center for Immunoglobulins, Spring- ence standard in all IgE assays. Because of lack of agree- field, Virginia. This method was capable of detecting concen- ment among various investigators as to the absolute con- trations as low as 1 mg/100 ml. All sera giving rings of pre- centration of IgE in the WHO reference standard (25), cipitate on the goat antihuman IgD and/or IgE (see below) all IgE data are expressed as units per milliliter, the stated agarose plates were also tested on agarose plates containing value of 9,346 U/ml in the WHO standard being used as either 10, 50, or 100 Al of normal goat serum/15 ml aga- a reference. Statistical nethods. All data were transformed loga- rithmically for statistical analysis, since concentrations of immunoglobulins G, A, and M have been shown to have a 'Abbreviations used in this paper: A Def, selective IgA logarithmic gaussian distribution (26). For the logarithmic deficiency; A-T, ataxia telangiectasia; CGD, chronic gran- transformation, undetectable IgD values were called 0.1 mg/ ulomatous disease of childhood; Hyp E, extreme hyper- 100 ml and IgE values 1 U/ml. Since both the IgD and immunoglobulinemia E and undue susceptibility to infection; IgE concentrations in the control groups were found to Hyp M, X-linked immunodeficiency with hyper-IgM; Nez, have multimodal distributions, however, the differences be- Nezelof syndrome or cellular immunodeficiency with normal tween group IgD and IgE concentrations or hyperimmunoglobulinemia; Non-X Ag, non-X-linked were tested by agammaglobulinemia; PS, purified IgE; SCID, severe com- the Mann-Whitney U test for differences of medians (27). bined immunodeficiency; T, thymus-derived; Trans Ag, Student's t test was also used to test differences between transient hypogammaglobulinemia; Var ID, variable im- group mean log IgD and IgE concentrations. 95%o confi- munodeficiency; W-A, Wiskott-Aldrich syndrome or im- dence intervals were obtained by taking the antilogs of munodeficiency with thrombocytopenia and eczema; X Ag, the mean logarithms ±2 pooled SD of the logs of the infantile X-linked agammaglobulinemia. data, as previously described (21). 158 R. H. Buckley and S. A. Fiscus TABLE I Serum IgD Concentrations in Immunodeficiency Patients

P value Geom. P value (Mann- Group Number Ages Range mean (t test) Median Whitney)

mg/100 ml Transient hypogammaglobulinemia 8 (3-20 mo) <1 <0.1 NS 0.1 NS Severe combined immunodeficiency 9 (3-17 mo) (<1-2) 0.1 NS 0.1 NS X-linked agammaglobulinemia 10 (3-16 yr) (< 1-20.6) 0.4 0.02 0.1 NS Non-X-linked agammaglobulinemia 15 (6-35 yr) (<1-14.4) 0.2 <0.0001 0.1 0.0007 X-linked immunodeficiency with 3 (7 mo-21 yr) (<1-5.1) 0.4 NS 0.1 NS Hyper-IgM Selective IgA deficiency 79 (5 mo-50 yr) (<1-39.3) 0.7 <0.0001 0.1 0.0005 Ataxia telangiectasia syndrome 7 (5-14 yr) (<1-19.2) 2.6 NS 5.6 NS Nezelof syndrome 3 (8 mo-3 yr) (2-22) 7.0 NS 7.8 NS Wiiskott-Aldrich syndrome 4 (8 mo-12 yr) (<1-7.8) 0.7 NS 1.4 NS Extreme hyperimmuno- 11 (3-31 yr) (2.7-159) 14.4 <0.0001 16.1 0.0004 globulinemia E Other variable immunodeficiency 6 (1-14 yr) (<1-163.4) 3.6 NS 7.4 NS Chronic granulomatous disease 10 (6 mo-17 yr) (<1-53.1) 4.8 NS 4.6 NS Normal infants 23 (6 wk-19 mo) (<1-1.6) 0.1 0.1 (0-0.6)* Normal children 105 (3-14 yr) (<1-36) 1.6 3.0 (0-70)* Normal adults 57 (21-55 yr) (<1-11.2) 2.4 - 4.6 (0-61)* * 95% confidence interval. RESULTS Var ID had IgD values well above the appropriate normal group bounds (Table II). 11 of the 20 patients in Scrumn IgD concentrations. Group median serum these three groups had IgD concentrations greater than IgD concentrations were found to be significantly de- 10 mg/100 ml, and only two had no detectable IgD. As pressed in patients with Non-X Ag and A Def when can be seen, elevated IgD was not always associated with compared with the appropriate normal group data (Ta- increased concentrations of the other types of immuno- ble I and Fig. 1). Group medians were also quite low globulins; in patients J. T., J. C., and D. C. it was as- in Trans Ag, SCID, X Ag, Hyp M, and W-A, although sociated with abnormally low concentrations of one or these differences did not prove to be statistically sig- more of the other classes. nificant in the Mann-Whitney U test. The group median Serum IgE concentrations. Group median IgE con- IgD concentration was significantly elevated in pa- centrations were significantly depressed in patients with tients with Hyp E; medians for A-T, Nez, and CGD pa- Trans Ag, SCID, X Ag, Non-X Ag, Hyp M, and A-T tients were also elevated but differences were not sig- when compared with the appropriate normal group in the U test. IgD was not de- nificant Mann-Whitney data III and Fig. 2). Group median IgE concen- tectable in the sera of a majority of individuals (Table in groups with very low mean IgD values, but three pa- trations were significantly elevated in patients with tients with X Ag, three with Non-X Ag, one with Hyp A Def, W-A, and Hyp E; Var ID and CGD median M, two with W-A (Fig. 1), and 39 with A Def had values were also elevated but the differences were not measurable quantities ranging from 1.4 to 39 mg/100 ml. significant in the Mann-Whitney U test. In groups with One patient each with Hyp E and Nez and three with low IgE, the mean values were all under 10 U/ml and IgD and IgE in Immunodeficiency 159 histories suggestive of atopy. One patient in the CGD group had an IgE value above the 95% confidence interval of the normal group (Fig. 2). The latter patient was not atopic but had multiple staphylococcal liver ab- scesses at the time the blood sample was obtained. Relationship between IgD and IgE concentrations. Since patients with Hyp E had the highest mean IgD E~~~~~~~~~ concentration of any of the groups, this raised the question of a possible positive correlation between the 10 concentrations of these two immunoglobulins. This as- E sociation was also seen in CGD patients and in Nez patient DR and Var ID patient DC. Nevertheless, the correlation was not borne out in the other groups, since patients with A-T had elevated IgD and decreased IgE, and patients with W-A and A Def had decreased IgD and increased IgE.

1.6 -XZ DISCUSSION Although IgD was discovered over 9 yr ago (28) and

P value Geom. P value (Mann- Group Number Ages Range mean (I Test) Median Whitney) U/ml Transient hypogammaglobulinemia 8 (3-20 mo) (2-31) 6 0.05 5 0.0269 Severe combined immunodeficiency 9 (3-17 mo) (<1-82) 2 <0.0001 2 0.0018 X-linked agammaglobulinemia 10 (3-16 yr) (<1-5) 2 <0.0001 1 <0.0001 Non-X-linked agammaglobulinemia 15 (6-35 yr) (1-10) 3 <0.0001 3 <0.0001 X-linked immunodeficiency 3 (7 mo-21 yr) (<1-2) 1 <0.0001 1 0.0016 with hyper-IgM Selective IgA deficiency 74 (5 mo-50 yr) (3-3,800) 124 <0.0001 174 0.0001 Ataxia telangiectasia syndrome 7 (5-14 yr) (<1-54) 7 <0.0001 10 0.0005 Nezelof syndrome 3 (8 mo-3 yr) (5-7,000) 55 NS 5 NS Wiskott-Aldrich syndrome 4 (8 mo-12 yr) (135-720) 381 <0.0001 487 0.0020 Extreme hyperimmuno- 11 (3-31 yr) (2.150-40,000) 11,305 <0.0001 12,362 <0.0001 globulinemia E Other variable immunodeficiency 6 (1-14 yr) (11-2,880) 142 NS 70 NS Chronic granulomatous disease 10 (6 mo-17 yr) (<1-3,160) 88 NS 100 NS Normal infants 12 (2-19 mo) (3-81) 18 - 25 (1-222)* Normal children and adults 106 (2-55 yr) (2-549) 55 - 55 (5-62 1)*

* 95% confidence interval.

IgD (30, 31) and that most of these lymphocytes (75- munodeficient humans. The finding in the present study 86%) also bear IgM (32). There is evidence that both of detectable IgD in only 39 of 79 (49%) A Def's as of these immunoglobulins are produced by the cells compared with its detection in 75 of 105 (71%) normal carrying them, as opposed to being nonspecifically ab- children, and 46 of 57 (81%) normal adults is similar sorbed to their surfaces (32). The simultaneous presence to the findings of Johansson, Hogman, and Killander of immunoglobulin molecules of two different heavy (11). This suggests that IgD deficiency may be common chain types on the surface of a single lymphocyte is among A Def patients. While IgD was found to be un- unique since, in general, lymphocytes bearing IgG or detectable in 85% of 78 patients with idiopathic hypo- IgA have only one class on their membranes (33). The gammaglobulinemia studied by Rowe, Crabbe, and finding of a high percentage of IgD-bearing lymphocytes Turner (12), concentrations up to 33 mg/100 ml were in the peripheral blood was also quite surprising since found in the remainder. This is in keeping with the find- normally concentrations of this protein in serum are ing in the present study of normal to high normal con- quite low (34) and very few plasma cells containing centrations of IgD in a few patients with X Ag and IgD can be found in lymphoid tissues (12). These ob- Non-X Ag. servations have led to speculation that IgD antibody Patients in this study who had the highest concentra- molecules may function primarily as membrane recep- tions of IgD did not bear any obvious clinical resem- tors which may send a signal to the lymphocyte that blance to each other, except that recurrent staphylococ- results in a differentiation pattern distinct from that cal infections predominated among the CGD and Hyp E triggered by the IgM receptor (32). Since abnormalities patients, and Var ID patients J. C. and D. C. In con- in lymphocyte differentiation have been implicated as trast, Var ID patient J. T., who had the highest serum the basis for deficiencies in production of other classes IgD concentration (163 mg/100 ml) had as his sole of immunoglobulins (34), it is possible that some of the clinical problem recurrent and severe pharyngeal in- abnormalities in serum IgD concentrations found in the fections; the latter were proven to be of streptococcal present study could be due to differentiation defects. etiology on a number of occasions. Despite this, the While several studies have been made of serum IgD patient had very low titers of anti-DNase B, anti-NAD- concentrations in normal individuals (25-37), very little ase, and antigroup A carbohydrate streptococcal antibod- is known about IgD levels in disease states or in im- ies. The restriction of this boy's infections to the naso- IgD. and IgE in Immunodeficiency 161 previously (12). The finding of elevated IgD in tuberculosis (38), leprosy (12), and in the CGD and Hyp E patients in the present study would suggest this. Con- trary to this is the fact that many other of the study patients who were chronically infected had low or undetectable quantities of IgD, including some of the CGD patients. Moreover, Rowe, McGregor, Smith, Hall, and Williams (37) found IgD concentrations to be normal in malaria and in members of a West African E (Gambian) community where chronic parasitic infesta- tion and infections are likely to be common. IgD was found to be normal in patients with various types of autoimmune diseases (12) but elevated approximately three- fold over normal in pregnant women (39). Li~~~~~~~-L The observed deficiency of serum IgE in X Ag, Non- X Ag, SCID, and A-T is in keeping with the findings of others (5-10) and is not surprising since all but the A-T have generally inadequate production of all or most types of immunoglobulins. Interest in the possible role Trans SCID X Ag Non-X Hyp A-T W-A CGD Ag Ag M 1,400- FIGURE 2 Serum IgE concentrations in X Ag, Non-X Ag, Trans Ag, Hyp M, SCID, A-T, W-A, and CGD. The cross-hatched area on the left represents the 95%O confidence interval for 12 normal infants; the normal geometric mean of 18 U/ml is indicated by the middle horizontal line. The cross-hatched area on the right represents the 95% confidence interval for 106 normal children and adults; the 5000 normal geometric mean of 55 U/ml is indicated by the middle horizontal line. Individual immunodeficient patient IgE values are depicted by the dots and the geometric means of the patient groups by the horizontal arrows. of the fact that adenoids pharynx is of interest in view E were shown by Rowe et al. (12) to have far greater numbers of IgD-containing plasma cells than human spleen, lymph nodes, or intestinal lymphoid tissue. Pa- 100: tient J. T. had his tonsils and adenoids removed at age 14 mo but required further removal of posterior pharyngeal lymphoid tissue at age 5 yr. Unfortunately, none of this tissue was examined by immunofluorescence for IgD-containing plasma cells. Membrane immunofluorescence studies of J. T.'s peripheral blood lymphocytes did, however, reveal an elevated percentage (19%) of IgD- bearing lymphocytes. The presence of a continued marked elevation of serum IgD in this patient several years after his adenoids were removed indicates that IgD is still being produced in very large quantity, since the 2or < 4 6 8 10 12 14 Adult half-life of IgD in serum is only 2.8 days (29). A serum Age in Years IgD concentration of this magnitude was observed by FIGURE 3 Serum IgE concentrations in 74 patients with Barth et al. (13) in an immunodeficient girl who also selective IgA deficiency. The cross-hatched area represents had markedly elevated serum IgM. None of the Hyp M the 95% confidence intervals for 106 normal children and patients in the present study, however, had elevated IgD adults studied in this laboratory; the normal geometric mean of 55 U/ml is indicated by the middle solid line. In- levels. dividual atopic A Def patient IgE values are depicted bythe The possibility that chronic infection alone could closed circles and the nonatopic A Def values by the open cause elevated concentrations of IgD has been raised circles. 162 R. H. Buckley and S. A. Fiscus TABLE IV Comparison of Serum IgE Concentrations in A topic and Nonatopic Patients with Selectize IgA Deficiency

P value Geom. P value (Mann- Group Number Range mean (I test) Median Whitney) U/ml Atopic A Def's 38 (56-3,800) 330 <0.0001 270 <0.0001 Non-Atopic A Def's 36 (3-430) 44 NS 52 NS N\ormal children and adults 106 (2-549) 55 55 (5-561)* $ 95%,G confidence interval.

of IgE in host defense was stimulated by the report of treatments appeared to be depression of T (thymus- Ammann, Cain, Ishizaka, Hong, and Good (40) in 1969 derived)-cell immunity, since other studies by these that susceptibility to infection in A-T patients was cor- workers showed that administration of syngeneic car- related with a combined deficiency of IgA and IgE but rier-specific T lymphocytes to such animals could abro- not with IgA deficiency alone. This correlation was not gate the enhanced IgE antibody production (46). In confirmed in a larger group of A-T patients studied by support of the possibility that overproduction of IgE may Polmar, Waldman, Balestra, Jost, and Terry (5), how- be related to depressed T-cell immunity in man is that, ever, nor was it found in three groups of non-A-T A Def except for the A Def patients in the present study, all patients (3, 5, 8). Indeed, the converse was found, e.g., immunodeficiency patients with excessive IgE production there was a very high frequency of respiratory tract dis- in this and other reports (4, 7, 42) have also had im- ease in A Def's who were not IgE deficient (5). More- paired cell-mediated immunity. It is possible that even over, healthy IgE-deficient patients have been found A Def patients may have a T-cell subpopulation deficit, (41) and as noted below, a number of examples have since they recently have been shown to have decreased now been found where undue susceptibility to infection percentages of T-cell rosettes (34) and impaired inter- is associated with abnormally elevated serum IgE con- feron production by phytohemagglutinin-stimulated centrations (4, 7, 42). lymphocytes (47). The elevated concentrations of IgE in our A Def popu- A third factor possibly related to increased IgE pro- lation are similar to those reported previously in a duction in certain of these immunodeficiency patients is smaller portion of the group (3). It would appear that a chronic infection, particularly with staphylococcal or- high incidence of atopy in these patients is the primary ganisms. Features of the nine additional patients with reason for this. Since most of the A Def individuals in extreme hyperimmunoglobulinemia E and undue suscep- the present and previous study were drawn from patients tibility to infection (Table II) discovered since the referred to an allergy clinic, however, it is impossible to original report (4) will be reported in detail elsewhere.' say whether the observed increased incidence of atopy In brief, all had lifelong histories of recurrent severe reflects an increase in atopy among A Def patients in staphylococcal and, in many cases, fungal infections, general. and all had evidence of depressed cell-mediated immunity. The elevated IgE concentrations found in the W-A Patients with CGD, and Var ID patients D. C. and A. P. patients in this report are in keeping with those found also had a high frequency of staphylococcal infections. by others (2, 6) and are possibly related to these pa- Elevated IgE was noted by Arbesman, Ito, Wypych, and tients' dermatitis. An alternative hypothesis, however, is Wicher (48) in a patient with chronic osteomyelitis, but that the impaired cell-mediated immunity in this condi- no organism was mentioned. Against a major role for tion, in the Hyp E patients, in Nez patient D. R., and in chronic infection per se in augmenting IgE production, Var ID patient A. P., is causally related to the aug- however, is the fact that most of the CGD patients in mented IgE production. A precedent for such a relation the present study had values within the 95% confidence is seen in the experimental work of Tada and coworkers interval for the normal group and we found elevated (43-45) who have produced enhanced IgE antihapten serum IgE concentrations in only 2 of 56 patients with antibody formation in rats by treating them with small cystic fibrosis.' doses of antithymocyte serum, 400 R whole body irradiation, adult thymectomy and splenectomy, or by giving various immunosuppressive drugs before or shortly after 2 Manuscript in preparation. immunization. The common facilitating factor in those ' Unpublished observations. IgD and IgE in Immunodeficiency 163 Although no clear patterns of infection susceptibility 9. Spitz, E., E. W. Gelfand, A. L. Sheffer, and K. F. associated with deficiencies or excesses of IgD and IgE Austen. 1972. Serum IgE in clinical immunology and allergy. J. Allergy. Clin. Immunol. 49: 337-347. production emerge from the observations in this re- 10. McLaughlan, P., D. R. Stanworth, A. D. B. Webster, port, it is hoped that the trends noted will prove helpful and G. L. Askerson. 1974. Serum IgE in immune de- in the future definition of biologic roles for these proteins. ficiency disorders. Clin. Exp. Immunol. 16: 375-381. 11. Johansson, S. G. O., C. F. Hbgman, and J. Killander. 1968. Quantitative immunoglobulin determination. Com- ACKNOWLEDGMENTS parison of two methods. Estimation of normal,- levels and levels in persons lacking IgA and IgD. Acta We are grateful to Dr. David S. Rowe for his donation of Pathol. Microbiol. Scand. 74: 519-530. sheep anti-Fc (ND) antiserum, to Dr. 0. Ross McIntyre 12. Rowe, D. S., P. A. Crabbe, and M. W. Turner. 1968. for giving us PS serum, to Dr. Mary Ann Passero for Immunoglobulin D in serum, body fluids, and lymphoid assistance in preparing the Fc(PS), to Dr. Roy Woods tissues. Clin. Exp. Immunol. 3: 77-490. for his gift of purified Bedore IgE paraprotein, to Dr. C. 13. Barth, W. F., R. Asofsky, T. J. Liddy, Y. Tanaka, E. Buckley for help with statistical analysis of the data, D. S. Rowe, and J. L. Fahey. 1965. An antibody de- and to Dr. Susan C. Dees and the many other physicians ficiency syndrome. Selective immunoglobulin deficiency who referred us patients for study or sent us their sera. with reduced synthesis of -y and a immunoglobulin We also acknowledge the skilled technical assistance of polypeptide chains. Am. J. Med. 39: 319-334. Mr. Craig P. Prokos and Mrs. Carolyn Stopford and the 14. Heiner, D. C., and B. Rose. 1970. A study of antibody excellent secretarial assistance of Mrs. Lora B. Whitfield. responses by radioimmunodiffusion with demonstration Supported by Asthma and Allergic Diseases Center of yD antigen-binding activity in four sera. J. Immunol. Grant (AI 12026-01), Allergic Diseases Academic Award 104: 691-697. 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